Taxol is a poorly water soluble alkaloid isolated from several species of Western Yew. Taxol exhibits antimitotic properties and is presently undergoing phase I clinical trials for the treatment of cancers. Taxol has been shown to be active against leukemia, colon, breast, melanoma, sarcomas, and Lewis lung tumor systems. Tarr et al. (1987) Pharm. Res. 4:162-165; Horwitz (1992) TIPS 13:134-131. In vitro studies indicate that concentrations of taxol (0.1-10.0 .mu.g/ml, stabilize microtubules, thus disrupting normal cell division. Rowinsky et al. (1990) J. Natl. Cancer Inst. 82:1247-1259.
Taxol is a complex diterpene having a taxane ring system with a four-membered oxetane ring and an ester sidechain at position C-13, as follows: ##STR1##
In an attempt to increase taxol's solubility and develop more feasible clinical formulations, investigators have acylated carbons of taxol's taxene ring at the 7-position and 10-position. These efforts have yielded compounds that retain activity. Rowinsky et al. (1990) J. Natl. Cancer Inst. 82:1247-1259.
Because of its poor solubility in water and many oils, taxol has been administered in formulations using cremophors. Cremophors are polyoxyethylated castor oils. The current Sigma taxol formulation most widely used consists of ethanol:cremophor EL:isotonic saline (5:5:90). The drug's solubility in this vehicle does not exceed 0.6 mg/ml and it remains physically stable only for a short time (3 hr). Therefore, large volumes of these formulations, with limited solubility, would have to be infused to obtain a desired total dose of 30 mg. Tarr et al. (1987) Pharm. Res. 4:162-165. The patient is usually required to check into a hospital and endure intravenous infusion for an extended period, such as twenty-four hours. Typically, taxol is administered intravenously in a preparation containing 30 .mu.g/ml over a period of twenty-four hours, followed by a week of rest and another dose. This is repeated two more times.
Further, the BASF cremophor EL (polyoxyethylated castor oil), is extremely toxic and has been shown to produced vasodilation, labored breathing, lethargy, hypotension and death in dogs. Rowinsky et al. (1990) J. Natl. Cancer Inst. 82:1247-1259. Anaphylactoid reactions attributed to the cremophor have also been observed. Green et al. (1987) Cancer Treat. Rep. 71:1179-1184.
Hypersensitivity reactions have been observed using the above formulation; one patient had a fatal reaction. It is unclear whether taxol itself or its cremophor vehicle is principally responsible for the hypersensitivity reactions. Rowinsky et al. (1990) J. Natl. Cancer Inst. 82:1247-1259.
Cosolvents have also been utilized in taxol preparations but require infusion times even longer than the currently-used formulation. Drugs with cosolvent formulations may precipitate if infused too fast.
In an attempt to overcome the taxol formulation problems using the toxic cremophor, and in an attempt to provide a formulation from which the active ingredient would not precipitate out from the aqueous solvent after IV administration, Tarr et al. (1987) Pharm. Res. 4:162-165, attempted to formulate taxol with Intralipid (trademark of RabiVitrum (formerly Cutter Medical) comprising soybean oil, lecithin, egg yolk phospholipids, and glycerol), a commonly used parenteral emulsion; however, the poor solubility of taxol in soybean oil (0.3 mg/ml) made this vehicle unsuitable.
Tarr et al. then made taxol emulsion formulations using triacetin, in which the solubility of taxol is 30 mg/ml, along with emulsifying agents L-alpha-lecithin, pluronic F-86 of BASF company, polysorbate 80 of Sigma Chemical Co., and ethyl oleate. Glyercol was also added to slow creaming. Toxicity of the formulation was observed, including lethargy, ataxia and respiratory depression in animal models, presumably due to the toxicity of the triacetin. The emulsion showed an intravenous LD50 of 1.3 ml/kg in mice. The tricetin emulsion initially gave a 1 .mu.m average diameter droplet and exhibited instability, separating into two phases at six months. Vigorous shaking again formed an emulsion having an average droplet size of 2 micrometers.
As taxol has been determined to be an especially effective anti-cancer agent, formulations which do not contain toxic ingredients and which allow delivery of pharmaceutically relevant dosages in a reasonable period of time, such as orally or by injection, are especially needed. Such formulations have not been previously available.
Methods and compositions for solubilizing pharmaceutically relevant dosages of taxol in pharmaceutically acceptable oils are therefore highly desirable objects of this invention.
The use of oil-in-water emulsions for delivery of taxol and its active analogs are needed to avoid problems of precipitation of I.V. solutions at the time of administration, increase bioavailability of orally administered taxol and prevent gastrointestinal upset. In nonemulsified form, taxol is degraded in the stomach. However, prior efforts to produce pharmaceutically-acceptable emulsions containing the taxol have failed due both to the relative insolubility of taxol in typical pharmaceutically suitable oils and due to the need for the use of toxic surface-active agents.
U.S. application Ser. No. 07/830,058 which is incorporated herein by reference, provides novel methods and compositions for forming pharmaceutical emulsions without using conventional surfactants. The use of these novel emulsification methods and compositions in combination with the novel solutions of taxol and its active analogs provided herein are objects of this invention.
Pharmaceutically acceptable oils useful in forming oil-in-water emulsions are well-known to the art and include vegetable, animal and marine oils. However, the poor solubility of taxol in most oils, such as safflower, olive and soybean oil (about 0.3-0.6 mg/ml), has prevented the use of such oils in previously-known taxol formulations.
Marine oils, especially those that are classified as ether lipids as opposed to triglycerides, are known to the art and include orange roughy, squalane, squalene and shark liver oil.